The specific aim of this project is to analyze the contribution of cytochrome P4502E1 (CYP2E1) to interindividual susceptibility to alcoholic liver disease (ALD) in Mexican-Americans. The long-term objective is to understand the molecular mechanisms underlying the development of, and the resistance to, ALD in Mexican-Americans. The c2 allele of the CYP2E1 gene is associated with the development of ALD in some ethnic groups. In Mexican-Americans, the c2 allele frequency is 16 percent. Four approaches will be taken to analyze the role of CYP2E1 in ALD. First, Mexican-American ALD patients (200 subjects) will be recruited and genotyped for CYP2E1. Phenotyping of CYP2E1 using chlorzoxazone will also be performed in a sub-set of both normal volunteers and ALD patients with different alleles. The association among ALD, CYP2E1 activity, and genotype will be determined. The genotype of aldehyde dehydrogenase (AlDH2) will also be examined to assess other another possible cause of ALD. Second, the inducibility of CYP2E1 by ethanol will be examined by phenotyping normal subjects and ALD patients who carry different alleles. For the normal subjects, phenotyping will be performed before and after consumption of ethanol. For the ALD patients, phenotype will be determined before and after the subjects have abstained from drinking. The relationship among genotype, inducibility of enzyme activity by alcohol, and development of ALD will be determined. Third, Mexican- American subjects (200 subjects) who abuse alcohol, but do not have ALD, will be genotyped for the CYP2E1 and ADH2 genes. Likewise, the inducibility of CYP2E1 by alcohol will be examined in subjects who have different alleles. Fourth, the CYP2E1 gene will be studied by PCR and sequencing in subjects whose genotype is associated with neither a given phenotype nor the development of ALD in order to identify other candidate genes that may be accounted for the cause of ALD. In addition, the presence of wild-type and mutant ubiquitin, which is responsible for degradation of CYP2E1, will be studied in control, ALD, and non-ALD subjects to determine if CYP2E1 activity is mainly controlled at the post-transcriptional level. The data generated from this study will lay the foundation for understanding the pharmacogenetic aspects of ALD in Mexican-Americans, the fastest growing minority population in the United States.